The main goal of this I/START proposal is the translational development of a novel PET radiotracer based on an endogenous opioid neuropeptide, b-endorphin, using an innovative and rapid 18F radiolabeling strategy. This is a multidisciplinary transitional project involving the expertise of the co-PIs in peptide chemistry, analytical chemistry, and in vivo opioid receptor pharmacology in non-human primates, as well as guidance and collaboration in radiochemical synthesis, PET imaging, and its analysis. b-endorphin is a major endogenous agonist at 5-opioid receptors (MOP-r), the target of addictive opioids such as heroin and prescription opioid analgesics such as oxycodone and morphine. MOP-r are also prominently involved in the downstream effects of cocaine and alcohol addiction, and also modulate the hypothalamic-pituitary-adrenal (HPA)-stress axis, which is part of the pathophysiology of addictive states. As a long-term objective, this radiotracer could therefore be used to determine how addiction or pain states affect functional b-endorphin distribution and receptor pharmacodynamics. This new radiotracer would complement the available knowledge obtained with currently available small molecule opioid radiotracers, by revealing changes in - endorphin distribution, pharmacodynamics, or systems level function due to addiction or pain states, or due to individual genetic variation in MOP-r. Such alterations can be mediated in central or peripheral pain pathways, in HPA-stress axis, or at the blood-brain barrier. Aim 1 focuses on the synthesis and optimization of a novel 18F-b-endorphin radiotracer using an innovative radiochemical synthesis, and its basic distribution in the periphery, hypothalamus, and possibly other parts of the CNS in PET scans in non-human primates, for translational relevance. Aim 2 would then determine key pharmacodynamic and distribution characteristics of this radiotracer, particularly opioid receptor selectivity and distribution across the blood-brain barrier. Significance and Impact: The novel strategy for radiolabeling a specific amino-oxy derivative of -endorphin would also have broader impact in neuroimaging as it is applicable to other neuropeptides and peptidic hormones and analogs thereof. 18F--endorphin has considerable potential significance as an imaging agent in addiction and pain medicine. In particular, this radiotracer could allow direct investigation of endogenous opioid regulation and distribution in addiction and pain states, as well as related functional changes in the HPA-stress axis. This would include the distribution and fate of endocrine b -endorphin, as well as unique aspects of endogenous opioid neuropeptide pharmacology, compared to that of exogenous compounds (including abused opioid drugs). Potentially unique aspects of -endorphin function to be directly evaluated with this radiotracer in future studies include blood-brain processes, and direct evaluation of a single nucleotide polymorphism (SNP) in MOP-r (A118G in humans, and its proposed non-human primate ortholog). This SNP affects individual human vulnerability in addiction and pain states, as well as HPA-axis function. PUBLIC HEALTH RELEVANCE: The main goal of this I/START proposal is the translational development of a novel PET neuroimaging radiotracer based on an endogenous (i.e., natural) opioid neuropeptide, b-endorphin, using innovative radiochemical synthesis methodology. This neuropeptide is a major endogenous compound acting at opioid receptors (e.g., the 5-opoid receptor), which are targets of abused opiates (e.g., heroin), as well as major prescription opioid analgesics (e.g., oxycodone, morphine). The development of this novel neuropeptide radiotracer will greatly expand our ability to image in vivo the function of the b-endorphin / opioid receptor system in addictive and pain states, conditions which cause massive morbidity and public health costs.